STRIATAL SUBSTRATES REGULATING SENSORY-GUIDED AND MEMORY-GUIDED BEHAVIORS Abstract Decision-making requires the continual integration of sensory evidence for and against alternative options, as well as the selection and execution of a motor output aimed at achieving a desired outcome. Activity in mutually antagonistic direct- and indirect-pathways of the striatum has long been hypothesized to regulate the selection of actions by exerting opposing effects on behavior. While activations of direct- and indirect-pathway neurons have recently been shown to produce opposing behaviors, it remains fundamentally unresolved whether endogenous activity in striatal pathways contribute directly to the generation of a motor output, or if they participate in cognitive processes influencing the decision towards a motor output. To address this question we will utilize a suite of modern neural circuit tools in mice performing two virtual reality (VR)-based navigation tasks that have identical motor requirements, but differ in their dependence on sensory- versus memory-guided behavior. Using this powerful behavioral approach we will carefully disambiguate simple motor processes from those involving the accumulation of evidence, a highly quantitative assay of working memory based decision-making. We further propose to exploit this unified task framework towards a comprehensive survey of the causal relationships and neural dynamics underlying sensory-guided motor output and memory- guided decisions in direct- and indirect-pathways across two striatal sub-regions (dorsomedial, DMS, or dorsolateral, DLS). First, using cell-type specific, optogenetic inhibition we will causally determine whether each pathway in DMS or DLS is necessary for sensory- and memory-guided motor outputs. Employing temporally limited, sub-trial inhibition we will further determine precisely when each pathway in each striatal sub-region supports memory-guided motor output. Finally, utilizing state-of-the-art 3-photon imaging for deep brain areas, we will examine how activity in DMS and DLS direct- and indirect-pathway neurons encodes information related to motor and cognitive operations supporting decision-making in the two tasks. Importantly, our task settings provide tremendous power to closely readout and quantify elemental motor and cognitive operations, allowing us to precisely measure which aspect(s) of motor output and decision-making depend on each striatal pathway and sub-region, and how dynamic patterns of neural activity map onto component processes sub-serving these behaviors. Our experiments will therefore provide a detailed and quantitative account of the causal mechanisms and neural correlates supporting sensory- and memory-guided behavior in the direct- and indirect- pathways of the DMS and DLS. Our findings promise to generate novel insight into basic motor and cognitive functions of striatal cell-types across striatal domains, an endeavor with tremendous significance for improving understanding of human disorders such as schizophrenia and Parkinson's disease, which exhibit divergent cognitive and motor deficits while sharing a core dysfunction in striatal circuitry.